Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the U.S. and is associated with an imbalance in proteolytic activity in the lungs. Treatment is largely aimed at symptom remediation using bronchodilators and corticosteroids, but these do not treat the underlying disease process. We are developing a gene-based therapy to treat COPD that supplements levels of alpha-1 antitrypsin (a potent anti-proteolytic protein) in at risk regions of the lungs. The studies proposed in the specific aims listed below will specifically test the anti- proteolytic potency, anti-inflammatory effects, and efficacy in preventing or reversing emphysema by expression of the AAT gene in mice. Specific Aims: 1. Determine time course of AAT gene expression in C57BL/6 mice following intratracheal instillation and intravenous injection of the human AAT gene formulated in a plasmid and combined with a monovalent cationic liposome. 2. Establish models of emphysema in other groups of mice through intranasal instillation of porcine pancreatic elastase. 3. Examine effects of AAT gene delivery on attenuation of emphysema in mice. Specifically, to determine whether or not emphysema development in mice can be avoided, attenuated, and/or reversed we will deliver the AAT gene as a lipoplex: 1) weekly prior to the initial dose of elastase; 2) in a single dose simultaneous with the initial dose of elastase; 3) weekly starting at approximately two weeks after elastase delivery (when emphysema is fully established); and 4) weekly during the two weeks prior to fully established emphysema.